胰岛素调控对于节食和进食的代谢和行为反应的一个新颖机制已被发现。在节食期间，神经肽阿立新（亦称“苯基二氢喹唑啉”）和MCH（黑色素浓缩激素）在“下丘脑外侧区”（大脑中传统中被认为是“进食中心”的区域）释放，在那里它们诱导有动机的行为和刺激食物摄取。
用小鼠所做的研究表明，阿立新和MCH的表达由转录因子Foxa2调控。进食之后，胰岛素信号作用会使Foxa2无效，使阿立新和MCH的生成停止。Foxa2的活性被永久打开的小鼠有更多的阿立新和MCH，吃的更多，身体更活泼，对胰岛素的敏感度也有所提高。打开肥胖小鼠身体中的Foxa2，会增加身体中瘦肉含量，减少脂肪含量。因此，通过药理手段阻断Foxa2的磷酸化，可能会增强身体活动水平，提高总体健康状况。（生物谷Bioon.com）
生物谷推荐原始出处：
Nature 462, 646-650 (3 December 2009) | doi:10.1038/nature08589
Regulation of adaptive behaviour during fasting by hypothalamic Foxa2
Jose P. Silva1,4, Ferdinand von Meyenn2,5, Jessica Howell1,2,5, Bernard Thorens3, Christian Wolfrum2 & Markus Stoffel1,2
1 The Rockefeller University, Laboratory of Metabolic Diseases, 1230 York Avenue, New York, New York 10021, USA
2 Swiss Federal Institute of Technology, ETH Zürich, Institute for Molecular Systems Biology, Wolfgang Pauli Strasse 16, 8093 Zürich, Switzerland
3 Center of Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland
4 Present address: Department of Neuroscience, The Scripps Research Institute, Scripps Florida, 130 Scripps Way, Jupiter, Florida 33458, USA.
5 These authors contributed equally to this work.
Correspondence to: Markus Stoffel1,2 Correspondence and requests for materials should be addressed to M.S.
The lateral hypothalamic area is considered the classic 'feeding centre', regulating food intake, arousal and motivated behaviour through the actions of orexin and melanin-concentrating hormone (MCH)1, 2, 3. These neuropeptides are inhibited in response to feeding-related signals and are released during fasting. However, the molecular mechanisms that regulate and integrate these signals remain poorly understood. Here we show that the forkhead box transcription factor Foxa2, a downstream target of insulin signalling4, 5, 6, regulates the expression of orexin and MCH. During fasting, Foxa2 binds to MCH and orexin promoters and stimulates their expression. In fed and in hyperinsulinemic obese mice, insulin signalling leads to nuclear exclusion of Foxa2 and reduced expression of MCH and orexin. Constitutive activation of Foxa2 in the brain (Nes-Cre/+;Foxa2T156Aflox/flox genotype) results in increased neuronal MCH and orexin expression and increased food consumption, metabolism and insulin sensitivity. Spontaneous physical activity of these animals in the fed state is significantly increased and is similar to that in fasted mice. Conditional activation of Foxa2 through the T156A mutation expression in the brain of obese mice also resulted in improved glucose homeostasis, decreased fat and increased lean body mass. Our results demonstrate that Foxa2 can act as a metabolic sensor in neurons of the lateral hypothalamic area to integrate metabolic signals, adaptive behaviour and physiological responses.
